Broad drug resistance. Types of drug-resistant tuberculosis and their therapy

Drug-resistant tuberculosis, as in the case of ordinary tuberculosis, is caused by Koch's bacillus. But there are differences in the disease, and there are many of them. For example, drug-resistant tuberculosis is a stronger and more resistant form than the usual disease. This is also expressed at the stage of treatment, when drugs intended for ordinary tuberculosis are ineffective before LUT. The disease itself is severe and worsens every year.

Behind Lately there are a considerable number of LUT forms, which are growing unhindered. If earlier this type of disease arose as a misuse of drugs and inconsistencies in treatment, now such a diagnosis haunts literally every second patient who first visits a phthisiatrician.

Patients at risk

Diseases can be experienced by people with such infections and diseases:

• persons who have been diagnosed with AIDS infection syndrome;
• people who are addicted to drugs and alcohol;
• members of the public who have problems with immunodeficiency and reduced immunity;
• people who do not have permanent residence and live in zones of complete or partial unsanitary conditions;
• persons imprisoned in prisons and pre-trial detention centers. A large amount of accumulation various people can lead to the spread of the disease. Also important role wins back the wrong method of treatment in places of deprivation of will.
• people who have previously fallen ill and are undergoing treatment, but who do not have real results in the recovery process.

The main symptoms of the disease include the following manifestations:

• chronic course of the disease, which have frequent exacerbations;
• if the x-ray shows not small tuberculous foci, but large stripes;
• tuberculosis can easily interact with bacterial or private diseases and infections, since sputum contains great amount microbacteria.

Causes of drug-resistant tuberculosis

The first of the causes of infection with drug-resistant tuberculosis can be attributed to the infection of one person from another who has this disease. The second group means infection during treatment. That is, people who have the usual form of tuberculosis can get some kind of mutation due to improper use of drugs or their ineffectiveness on the disease and its focus.

Due to the treatment, the composition of bacteria that create a mutation and do not take in the future could change. regular forms prevention. But along with ordinary bacteria, there will always be those that have defects and do not perceive medicines as a threat. If we take into account the fact that at least one hundred million bacteria are simultaneously located in only one focus of tuberculosis, then mutational forms are also necessarily located in them. infectious bacteria. It is they who will be resistant to all drugs known in the world.

If the healing process goes in the right direction and no errors are allowed, then the mutation bacteria will not play any role. Again, with improper treatment, if: the courses of treatment were completed ahead of time, the drugs were received in small doses, the drugs were selected incorrectly or the combination of drugs did not meet the standards, the bacteria were of the wrong content in relation to the usual ones, not the same dangerous bacteria, becomes larger. As a result, the disease develops much faster and the forms of bacteria acquire a viable appearance, which helps them to multiply rapidly.

Signs of LUT during treatment

The patient begins to cough with phlegm. It can also be expectoration accompanied by blood leakage, excessive sweating, a sharp decline in weight, feeling of weakness. The doctor will be able to tell the difference between LUT even before receiving the bacterial susceptibility test.

It is worth understanding that conventional drugs that treat tuberculosis simple type, are not cured, because the mutated bacteria are no longer susceptible to drugs. The doctor determines further treatment individually. Since the specialist needs to find out individual structure patient, as well as to see the threshold of his sensitivity to drugs. The course of treatment can last from a six-month examination to two years of therapy. chances of getting rid of similar illness make up approximately 50-80%, depending on the condition of the patient.

Remember that most reserve drugs are toxic, so they can provoke side effects that lead to long-term anguish for the patient. Sometimes doctors resort to surgical intervention during treatment, that is, a part of the infected lung is cut out.

But the basic principles of treatment remain the same:

1. continuity of treatment
2. its duration,
3. application various kinds drug combinations.
4. control by medical professionals.

Despite the fact that there is a breakthrough in medicine today and new drugs are appearing, doctors cannot completely cure MDR TB, as it is resistant to many drugs. It is usually treated conservative methods. This disease is in second place in terms of mortality among patients. Also, over time, new types of it appear. These types are distinguished by the fact that they have resistance to almost all drugs that exist today and are designed to fight tuberculosis.

Tuberculosis today can only be treated with the use of modern drugs, which provide strong impact on the body. But with the advent of such focal tuberculosis lungs also began to adapt to them and gain stability. This form is called multidrug-resistant tuberculosis.

In order to get rid of such tuberculosis, there are many medicines. One of these is Rifampicin. Other means are also used, which already belong to the second group. These are Cycloserine or Prothionamide and others.

Depending on the susceptibility of the disease to certain types drugs began to be divided into the following groups:

• resistant disease to one type of drug;
• resistance to two or more types of drugs. This form is common in 80% of patients;
• pathology resistant to all types of drugs that are used today.

The occurrence of MDR disease

Not yet today complete information about how many patients have focal pulmonary tuberculosis. In past years, there were about 500,000 people who suffer from it. It looks the same as ordinary tuberculosis, but it is practically incurable. Only a few are lucky to be cured of this form of tuberculosis. The patient cured at the same time still has to sit on the pills so that the symptoms do not worsen. Most patients with this form live in India and Russia.

How to diagnose initial stage focal pulmonary tuberculosis is quite severe, then there are few cases of recovery. Such patients a large number of, and therefore scientists continue to look for other ways to cure this severe form diseases.

It is also noted that for the occurrence of this type there are several reasons that relate to both social and medical:

• definition of the disease at its late stage. This makes it possible for tuberculosis to develop for a long time and infect others;
• poor-quality analysis in laboratories;
• irregular intake of medications;
• incorrectly defined therapy;
• the quality of treatment is low (use of expired medicines, incorrect dosage);
• poor adaptation of drugs by the patient's body;
• incomplete course of treatment.

Since there is a surge of infections with this form, it becomes more difficult to treat it. The causative agent of infection is constantly mutating, and therefore it is more difficult to identify it. In addition, it is difficult to initially choose the right the right drugs For timely treatment. It has been noted that the disease can be transmitted by airborne droplets with pre-existing resistance to certain drugs.

Doctors say that focal pulmonary tuberculosis is not critical for the patient. Healing is possible. The success of the elimination depends on many factors. First of all, these are correctly selected drugs.

It is important to immediately start using more aggressive medications, the effect of which can be equated to chemotherapy. Although they can cause many side effects and cost more conventional means they are effective. But, since not every organism can tolerate side effects, and not every person is able to buy such expensive medicine, they are rarely used.

Signs of the disease and its development

Symptoms of MDR tuberculosis are almost the same as usual:

• rapid fatigue of the body;
• high temperature;
• cough with secretions;
• sweating;
• weight loss;
• dyspnea;
• heaviness in the chest area.

But such symptoms may not always indicate tuberculosis. They just have to be a reason to see a doctor and get tested. You will need to take tests in the laboratory to determine the type of infection. The presence of MDR disease can be judged by the following points:

• tests remain positive for a long time after treatment;
• the patient's condition is constantly deteriorating, despite the therapy;
• x-rays confirm the development of pathology.

Also, the cause of the manifestation of MDR may be improperly performed initial therapy. When testing, an analysis is made for the resistance of the disease to certain drugs. Such diagnostics are not carried out quickly and can take about 6-7 days.

At-risk groups

Statistics confirm that this type is difficult to treat in many countries of the world. If Koch's wand enters the human body, then how quickly it begins to develop depends on immunity and general condition health. The environment also plays an important role.

The following categories of people are at risk of contracting MDR tuberculosis (those who):

• has a lot of contact with such patients, especially in a closed room;
• lives with HIV-infected people;
• is in prison or hospital;
• who has stomach problems;
• is ill with tuberculosis and has not been fully treated.

Treatment and features

Patients with this form should be aware that treatment in some cases can be long and difficult. This may take two years or more. During such a period, it is important to strictly follow all the prescriptions and recommendations of the doctor.

Therapy is important to carry out only in a hospital. But this is determined by the doctor in each case individually. After mandatory testing, a person is assigned a personal therapy regimen. It is based on the type of pathogen and the presence of other diseases in the body.
Intensive treatment can last 6 months. During this period, the patient will receive injections and take medication. Then the treatment regimen changes. Next stage treatment can already last about a year and a half.

It is also worth remembering here that the drugs that are taken for treatment this disease, toxic, and therefore can have serious side effects. Some medicines can be generally unpleasant for the patient and dangerous to his life. The patient will be cured of such a pathology only if he unquestioningly fulfills all the requirements of the doctor.

Prevention

For the prevention of any form of the disease, it is important to adhere to such points:

• to refuse from bad habits;
• Healthy food;
• maintain your immunity at the proper level;
• often be in the fresh air;
• exercise regularly.

To prevent the development of MDR tuberculosis, it is worth fully undergoing treatment for initial stage. To do this, you need to contact the doctor in time and follow all his recommendations, taking necessary funds. There should be no gaps in treatment. And it is also important to bring it to the end.

If any means prescribed by the doctor do not give the expected result, then it is important to immediately tell the doctor about this. The sooner he can reconsider therapy, the better better result from treatment. This will also prevent the development of the disease.

RIA AMI

About the reasons for the appearance of medicinal sustainable forms Irina Vasilyeva, chief phthisiatrician of the Ministry of Health of the Russian Federation, head of the phthisiology department of the Federal State Budgetary Institution Central Research Institute of Tuberculosis, and ways to combat them, tells:

Drug resistance develops when treatment is not carried out correctly or not for long enough. Treatment of tuberculosis is long - at least 6 months. If after 4 months the patient quits treatment, then some sticks survive. They mutate, become stronger, and give rise to new populations of bacteria that are resistant to these drugs. The wrong combination of drugs or low-quality drugs can also lead to the emergence of drug resistance.

According to 2012 data, about 20% of new cases were infected with multidrug-resistant mycobacteria. Among those previously treated, this percentage reaches 39%. And there are more and more such cases in the structure of morbidity every year.

If a patient relapses, then most likely we are talking about the drug-resistant form, since relapse usually occurs in those who are not well treated. Koch's rods that survive as a result of such treatment become resistant to drugs, therefore, for the treatment of such cases, special efforts. Any diseases that reduce immunity also lead to relapse.

In addition to multidrug-resistant forms, there are also extensively drug-resistant forms that are extremely difficult to treat. In this case, both first-line drugs and, partially, second-line drugs are powerless. Here we need a massive combination of both anti-tuberculosis and antibacterial drugs effective against Mycobacterium tuberculosis, the treatment is longer and more expensive.

Drugs for the treatment of tuberculosis are divided into several groups. First-line drugs are most effective in suppressing microbacteria sensitive to all drugs. Currently, a combination of 4 drugs is used to treat tuberculosis.

If at least two of the most important drugs stability arises in the first row, it is necessary to prescribe less effective and more toxic drugs second row. Nevertheless, they also work, but the course of treatment is lengthened, complicated, and its effectiveness is reduced. If they do not help, then third-line drugs are used.

In Europe, the current success rate for treating multidrug-resistant TB is 49%. And in our clinic - Central Research Institute tuberculosis - the success rate in the treatment of multidrug-resistant tuberculosis reaches 96%.

This is a very high percentage. If we talk about the data for the country, then the effectiveness of the treatment of drug-resistant tuberculosis is not very high. Usually, this is influenced by cases of a patient’s withdrawal from treatment, if he was discharged ahead of schedule, went into unauthorized territory, left for another territory ...

In our clinic, people come who, as a rule, have experience of unsuccessful treatment in the field. And they definitely don't come off. We have practically no "broke off" (less than 1%). In addition, our Institute practices complex treatment. Apart from therapeutic treatment, other methods are also used: surgical, bronchoblocking and pathogenetic methods treatments that increase the body's resistance to infection. Such old but true methods as collapsotherapy are also used.

As for drug treatment, it is the same everywhere. The drugs are the same. There is no such thing that we have these drugs, while others do not. Just important individual approach for each specific case.

No one has been working on the creation of new drugs for the treatment of tuberculosis for 20 years. However, after several outbreaks of tuberculosis in the early 90s, both foreign and domestic pharmaceutical companies began research in this direction. But this is a lengthy process: usually from the beginning scientific research several decades pass before its results are put into practice.

However, in 2013 World Organization Healthcare approved for use one of the new anti-tuberculosis drugs with a fundamentally new mechanism of action - Bedaquiline. This is a foreign development of Janssen. We also have it registered. Russian manufacturers adopted the technology, and this year the drug will already be produced in our country.

The drug has passed a long-term study around the world (several centers of our country also participated in the trials) and showed high efficiency. But one drug will not save you from tuberculosis, you need a combination of them. If new drug to attach to the old ineffective scheme, then we will only harm the patient. The regimen should use at least 4 drugs that respond to Koch's rod, and we usually prescribe a combination of 5-6 drugs.

To properly treat, you need a good microbiological diagnostics aimed at determining the properties of Mycobacterium tuberculosis, which will be affected by drugs. Only after the sensitivity or resistance of a particular mycobacterium in a particular patient has been determined, can the correct adequate treatment be prescribed.

We currently have implemented modern technologies By quick identification drug resistance of mycobacterium tuberculosis, which allows us to target the infection by prescribing exactly the combination of drugs that will work successfully for a particular patient.

Traditional methods for detecting drug resistance are quite lengthy. It takes three months to grow a bacillus and determine resistance. That is, all this time the patient can be treated, but it turns out that this treatment does not work, because the stick is resistant to the drugs used.

New accelerated molecular genetic diagnostic methods within a few hours (in last resort, two days) determine resistance to one or two of the most important drugs. There is also a method of accelerated culture studies to identify resistance to the entire spectrum of first and second line drugs.

For this, it is used automated system"Baktek", which allows you to quickly grow mycobacteria - in 2 weeks instead of 2 months. It takes a few more days to determine drug resistance. That is, after 3 weeks we already know to which drugs there is sensitivity, and to which - resistance, and we prescribe an individual combination only of those drugs to which the mycobacterium reacts.

This is, of course, great progress. Now we are trying to introduce these technologies in all regions of the country. Today everyone regional center uses one or the other new technology on the accelerated determination of sensitivity and resistance of mycobacteria. But if the region is large, this is not enough.

Now 93.6% of patients are covered by testing for drug resistance by one method or another. But accelerated diagnostics is not yet used everywhere. We are currently working to accelerated methods diagnostics have become available to every patient, no matter where he lives. Then the correct treatment will be prescribed.

V.Yu. Mishin

Drug resistance to anti-tuberculosis drugs is one of the most significant manifestations of MBT variability.

WHO classification (1998) office can be: monoresistant- to one anti-tuberculosis drug; multiresistant- to two or more anti-TB drugs, but not to a combination of isoniazid and rifampicin (the most effective medicines having bactericidal action at the MBT); multi-drug resistant- at least a combination of isoniazid and rifampicin;

By clinical classification V.Yu. Mishin (2000), patients who secrete MBT are divided into four groups:

• patients excreting MBT, sensitive to all anti-tuberculosis drugs;
• patients excreting MBT resistant to one anti-tuberculosis drug;
• patients excreting MBT resistant to two or more anti-TB drugs, but not to the combination of isoniazid and rifampicin;
• patients isolating multi-resistant MBT to at least isoniazid and rifampicin, which are divided into two subgroups:

1. patients excreting MBT resistant to isoniazid and rifampicin in combination with other main anti-tuberculosis drugs: pyrazinamide, ethambutol and / or streptomycin;
2. patients excreting MBT resistant to isoniazid and rifampicin in combination with other main and reserve anti-tuberculosis drugs: kanamycin, ethionamide, cycloserine, PAS and / or fluoroquinolones.

The main mechanisms for the development of MBT drug resistance to anti-tuberculosis drugs are mutations in the gene responsible for the synthesis of the target protein of the drug, or overproduction of metabolites that inactivate the drug.

In a large and actively breeding myco bacterial population there is always a small number of drug-resistant spontaneous mutants in the ratio: 1 cell mutant per 10 8 resistant to rifampicin; 1 cell mutant per 10 5 - to isoniazid, ethambutol, streptomycin, kanamycin, fluoroquinolones and PAS; 1 mutant per 10 3 - to pyrazinamide, ethionamide, kacreomycin and cycloserine.

Taking into account the fact that in the cavity the size of the mycobacterial population is 10 8 , there are mutants to all anti-tuberculosis drugs there, while in the foci and encapsulated caseous foci - 10 5 . Because most mutations are specific to individual drugs, spontaneous mutants are generally resistant to only one drug. This phenomenon is called endogenous (spontaneous) MBT drug resistance.

When conducting proper chemotherapy mutants practical value do not have, but as a result improper treatment When patients are prescribed inadequate regimens and combinations of anti-tuberculosis drugs and do not give optimal doses when calculating mg / kg of the patient's body weight, the ratio between the number of drug-resistant and susceptible MBT changes.

There is a natural selection of drug-resistant mutants to anti-tuberculosis drugs with inadequate chemotherapy, which, with prolonged exposure, can lead to a change in the MBT cell genome without reversibility of sensitivity. Under these conditions, the reproduction of mainly drug-resistant MBT occurs, this part of the bacterial population increases. This phenomenon is defined as exogenous (induced) drug resistance.

To date, almost all MBT genes that control drug resistance to anti-tuberculosis drugs have been studied:

Rifampicin acts on DNA-dependent RNA polymerase (groB gene). Resistance to rifampicin in the vast majority of cases (more than 95% of strains) is associated with mutations in a relatively small fragment. The size of this fragment is 81 base pairs (27 codons). Mutations in individual codons differ in their meaning. So, with mutations in codons 526 and 531, high level resistance to rifampicin. Mutations in codons 511, 516, 518 and 522 are accompanied by low level resistance to rifampicin.

Isoniazid essentially a prodrug. For manifestation antibacterial activity the drug molecule must be activated inside the microbial cell, however chemical structure The active form of isoniazid has not been definitively identified. Activation occurs under the action of the catalase/peroxidase enzyme (katG gene). Mutations in this gene (usually at position 315), leading to a decrease in enzyme activity by 50%, are found in approximately half of isoniazid-resistant MBT strains.

The second mechanism for the development of MBT resistance to isoniazid is hyperproduction of action targets. active forms drug. These targets include proteins involved in the transport of mycolic acid precursors and its biosynthesis: acetylated carrier protein (aspM gene), synthetase (kasA gene), and reductase (inhA gene) of the carrier protein.

Mycolic acid is the main component of the MBT cell wall. Mutations are usually found in the promoter regions of the listed genes. The level of resistance is associated with overproduction of targets and, as a rule, is lower than with mutations in the catalase-peroxidase genes.

Ethionamide (protionamide) also causes mutations in the inhA gene. This is because isoniazid and ethionamil share a common precursor with nicotinamide, and ethionamide resistance is sometimes acquired along with isoniazid resistance. Ethionamide is a prodrug and requires activation by an enzyme that has not yet been identified.

Pyrazinamide, like isoniazid, is a prodrug, since their common precursor is also nicotinamide. After passive diffusion inside the microbial cell, pyrazinamide is converted to pyrazinoic acid by the action of the enzyme pyrazinamidase (pncA gene). Pyrazinoic acid, in turn, inhibits biosynthetic enzymes fatty acids. In 70-90% of strains of mycobacteria resistant to pyrazinamide, mutations are found in the structural or promoter regions of pyrazinamide.

Streptomycin causes two types of mutations leading to modification of the antibiotic binding site with the small subunit (I2S) of the ribosome: mutations in the genes encoding the 16S rRNA (rrs) and the genes encoding the 12S ribosomal protein (rspL). There are more rare group mutations in ribosome genes that increase MBT resistance to streptomycin so much that these mutants are called streptomycin-dependent, because they grow poorly until streptomycin is added to the nutrient medium.

Kanamycin (amikacin) causes mutations encoding the rrs genome when adenine is replaced by guanine at position 1400/6S of the rRNA.

Ethambutol acts on the etbB protein (arabinosyltransferase), which is involved in the biosynthesis of MBT cell wall components. Resistance to ethambutol in the vast majority of cases is associated with a point mutation at codon 306.

Fluoroquinolones cause mutations in the DNA gyrase genes (gyrA gene).

Therefore, in clinical practice it is necessary to investigate drug sensitivity and, based on the results of these data, select the appropriate chemotherapy regimen and compare its effectiveness with the dynamics of the tuberculous process.

In addition to this, it stands out primary drug resistance MBT as resistance, determined in patients not taking anti-tuberculosis drugs. In this case, it is assumed that the patient was infected with this strain of MBT.

Primary multidrug resistance of MBT is characterized by the state of the mycobacterial population circulating in a given area, and its indicators are important for assessing the degree of intensity of the epidemic situation and developing standard chemotherapy regimens. In Russia, at present, the frequency of primary multidrug resistance in certain regions is 5-15%.

Secondary (acquired) drug resistance is defined as MBT resistance developing during chemotherapy. Acquired drug resistance should be considered in those patients who had susceptible MBT at the beginning of treatment with the development of resistance after 3-6 months.

Secondary multidrug resistance of MBT is objective clinical criteria ineffective chemotherapy; in Russia it is 20-40%.

Mechanisms of drug resistance formation.

~ enzymatic inactivation of the antibiotic

~ change in the structure of the target for the antibiotic

~ hyperproduction of the target (change in the agent-target ratio)

~ active release of the antibiotic from the microbial cell

~ change in cell wall permeability

~ Enabling a "metabolic shunt" (exchange bypass)

Variants of MBT drug resistance.

monoresistance– resistance to one anti-tuberculosis drug (ATD).

Polyresistance is MBT resistance to any two or more anti-TB drugs without simultaneous resistance to isoniazid and rifampicin.

Multidrug resistance (MDR, MDR) is resistance to the action of isoniazid and rifampicin simultaneously, with or without resistance to other anti-TB drugs. These strains of Mycobacterium tuberculosis are given Special attention, since the treatment of patients in whom the process is caused by such strains is very difficult. It is long, expensive and requires the use of backup drugs, many of which are expensive and can cause severe adverse reactions. In addition, multidrug-resistant strains cause severe progressive forms of the disease, often leading to poor outcomes.

Extensive drug resistance (XDR, XDR, extreme DR) is the simultaneous resistance of MBT to isoniazid, rifampicin, injectable aminoglycosides and fluoroquinolones.

Total drug resistance- resistance to all anti-TB drugs.

Cross drug resistance is a situation where resistance to one drug entails resistance to other drugs. Especially often, cross-LU is noted within the aminoglycoside group.

Methods for determining LU MBT.

Determination of the spectrum and degree of resistance of mycobacteria to anti-tuberculosis drugs has importance for the tactics of chemotherapy of patients, monitoring the effectiveness of treatment, determining the prognosis of the disease and conducting epidemiological monitoring of drug resistance of mycobacteria within a particular territory, country and the world community. The degree of drug resistance of mycobacteria is determined in accordance with the established criteria, which depend both on the anti-tuberculosis activity of the drug and its concentration in the lesion, the maximum therapeutic dose, pharmacokinetics of the drug and many other factors.

The cultural method makes it possible to determine the sensitivity and resistance of MBT to anti-tuberculosis antibiotics. The most common method for determining the drug resistance of mycobacteria is to be carried out on a dense culture medium Levenshtein-Jensen.

All methods for determining drug resistance are divided into two groups:

Currently, to determine the drug sensitivity of mycobacteria to anti-tuberculosis drugs in international practice, they use following methods:

- proportion method on Levenshtein-Jensen medium or on Middlebrook 7H10 medium

- the method of absolute concentrations on a dense egg medium of Levenshtein-Jensen

- resistance coefficient method

- radiometric method Bactec 460/960, as well as other automatic and semi-automatic systems

- molecular genetic methods for detecting mutations (TB biochips, GeneXpert)

Absolute concentration method in most cases used for indirect determination of drug resistance. The results of the determination of drug resistance by this method on the Levenshtein-Jensen medium are usually obtained no earlier than 2 - 2.5 months after sowing the material. The use of the nutrient medium "New" can significantly reduce these terms.

For the method of absolute concentrations, the appearance over 20 cfu mycobacteria on a nutrient medium containing medicinal product at a critical concentration, indicates that this strain of mycobacteria has drug resistance.

A culture is considered sensitive to a given concentration of the drug if less than 20 small colonies have grown in a test tube with a medium containing the drug at abundant growth in the control tube.

A culture is considered resistant to the concentration of the drug contained in this tube if more than 20 colonies have grown in the tube with the medium (“confluent growth”) with abundant growth in the control.

proportion method. The method is based on a comparison of the number of mycobacteria of the isolated culture grown in the absence of the drug and in its presence at critical concentrations. To do this, the prepared suspension of mycobacteria is diluted to a concentration of 10 -4 and 10 -6 . Both dilutions of the suspension are inoculated on a nutrient medium without the drug and on a set of media with different drugs. If more than 1% of colonies grown on the medium without the drug grow on the medium with the drug, the culture is considered resistant to this drug. If the number of CFU resistant to this drug is less than 1%, the culture is considered susceptible.

Resistance coefficient method. This method is based on determining the ratio of the minimum inhibitory concentration (MIC) determined for a given strain of a particular patient to the MIC of a drug-susceptible standard strain. H 37 Rv tested in the same experiment. In this case, the strain H 37 Rv is used not to control the experience, but to determine possible variations in the setting of the test. From this point of view this method is the most accurate of the three above, but due to the need to use a large number of test tubes with a nutrient medium, it is also the most expensive. The latter circumstance sharply limits its application.

VASTES system. For this method, the absolute concentrations of drugs in the finished liquid nutrient medium are used. Results are recorded automatically.